Ophthalmic drug delivery system and method

ABSTRACT

An ocular device comprising a biodegradable, and absorbable body configured in a shape for implanting
         directly exterior and anterior to a crystalline lens capsule in a patient&#39;s eye shaped in a C configuration or a ring configuration to stably lay on zonules or the anterior lens capsule or an intraocular lens (IOL) between an iris and an outer surface of the lens capsule, or   in the choroid shaped in straight rod configuration or in a snake-shaped semicircle configuration to follow the inside curvature of the sclera and readily position inside the suprachoroidal space, or   under the retina shaped in a rod configuration or a semicircle configuration
 
the device comprising a deformable material such that the device is folded upon implantation, the device optionally containing an ocular therapeutic agent released upon implanting in the patient&#39;s eye.

This application is a CIP of U.S. application Ser. No. 12/611,682 filed Nov. 3, 2009, which claims priority from U.S. Application No. 61/114,143 filed Nov. 13, 2008, the contents of which are expressly incorporated by reference herein in its entirety.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE shows a embodiments of the device.

Known methods of drug delivery to the eye have drawbacks, as the following illustrations demonstrate. Topical drug deliver must be repeated many times on a daily basis because of low or slow penetration. Compliance is also a problem. Subconjunctival drug delivery can be painful and has slow drug penetration. Intravitreal drug delivery has a short duration, typically of 2 to 30 days, so additional intervention and/or repeated injections are needed. The possibility of potential infections and retinal injury are also problems. Scleral implants and trans-scleral implants have not been attempted or tested. The implanted devices usually are made of polymers; there is usually slow intraocular penetration when polymers are injected into the eye. The vitreous usually requires additional intervention with attendant potential complications, such as infection, retinal injury, etc.

Method of intraocular delivery of various therapeutic agents and methods are disclosed in Peyman et al., Retina, The Journal of Retinal and Vitreous Diseases 29 (2009) 875-912, which is expressly incorporated by reference in its entirety.

The disclosed system and method uses the capsular bag, obtained during or after cataract extraction, as a polymeric slow release drug delivery system and method. It is used for drug delivery and for simultaneous support for the lens capsule.

The inventive system is used during or after intra-ocular surgery for cataract extraction in the same session. After an opening in the anterior chamber is made, a circular area of the anterior capsule is removed to extract the lens cortex and nucleus.

In one embodiment, the system and method is used post-surgically to prevent or to treat inflammation. After surgery, most if not all eyes have some inflammation for which treatment is administered. For example, all patients who have diabetic retinopathy have post-surgical ocular inflammation. All patients who have a previous history of uveitis have more excessive inflammation.

In one embodiment, the device is a capsular ring of any size configured in a shape for implanting outside the crystalline lens. Thus, the device is not dependent on removal of the crystalline lens. In this embodiment, the device is intraocular but is extralens, it is external to the lens. It is supported in the eye by the lens zonules or ciliary body.

In one embodiment, the device is a capsular ring of any size configured in a shape for implanting over the lens capsule having an intraocular lens. In this embodiment, where the eye contains an intraocular lens, the device is configured for implanting between the iris and the outer part of the lens capsule.

It is important that the device shape fits its position, that is, its location, inside the eye. The length of the device fits a large space inside the eye, and provides a longer duration of agent release over a wider area inside the eye than known devices.

In one embodiment, the device is configured for implanting anterior to the lens. In this embodiment, the device is configured either C-shaped or ring shaped to lay on the zonules or the anterior lens capsule or the intraocular lens (IOL). Any other device shape would not be stable in this position, that is, this location.

In one embodiment, the device is configured for implanting in the choroid. In this embodiment, the device is configured either as a rod or as a snake-shaped semicircle. In these configurations, the device follows the inside curvature of the sclera and can readily snake inside the suprachoroidal space. Any other device shape would be difficult to configure in the suprachoroidal space, and could penetrate the choroid and the retina resulting in serious complications. Any other device shape may not sufficiently large to cover a relatively large area.

In one embodiment, the device is configured for implanting under the retina, that is, for subretinal implantation. In this embodiment, the device is configured either as a rod or as a semicircle, following the curvature of the retina and the subretinal space. Although a circular device may be implanted under the retina, implanting would be difficult. A circular device would not follow the retinal curvature and would bulge the retina.

In all embodiments the device is biodegradable, also termed bioadsorbable; no foreign body remains in the eye after the device is absorbed.

The FIGURE shows various embodiments of the device. The device is rod shaped and may be straight, curved, C-shaped, closed loop, Its length ranges from 1 mm to 60 mm inclusive. In one embodiment, its length ranges from 15 mm to 600 mm inclusive. Its diameter ranges from 30 micrometers to 3 millimeters inclusive and is round, flat, bead-shaped, etc. The device is made of biodegradable polymers that contain and release agent contained within the device and/or within the polymers. In one embodiment the device is solid. In one embodiment the device is not-solid. In either embodiment, the device may be sized to be between 8 mm diameter and 18 mm diameter, inclusive.

The device is shaped as a rod, tube, open loop, or closed loop. In embodiments where the device is a rod, the device can be a solid rod or a hollow tube with closed ends. The device is folded for easy implanting through an incision that is as small as 1 mm. The nanlded over the lens capsule in the posterior chamber. For implanting, a viscoelastic substance is also implanted for lubrication and ease of implantation, as known to one skilled in the art. Once the device is it in place, the device is unfolded.

For a suprachoroidal implantation application, the device is shaped as a rod, tube or open loop. It is not shaped as a closed loop. The device is implanted under the sclera over the ciliary body or the choroid of the eye through a small incision, preferably in the sclera at the plars plana area 1 mm to 4 mm behind the limbus of the cornea/sclera junction, or anywhere else in the sclera. The incision reaches the ciliary body/choroid. The space between the ciliary body/choroid and the sclera is called suprachoroidal space. The device which has a semicircular or straight rod configuration is threaded in the suprachoroidal space in any desired direction toward any meridian. The resilient structure of the device assists in moving it in this space to the desired length. Because of its round tip, it cannot penetrate the choroidal vessels but follows the suprachoroida space when pushed against the resilient sclera. Its location can also be verified by indirect ophthalmoscopy. After the implantation, the scleral incision is closed with a suture.

For a subretinal implantation application, the device is shaped as a rod, tube, or semicircle. The device is implanted through a pars plana vitrectomy through the sclera. A subretinal bleb is created using a balanced saline solution at the desired retinal location, e.g., in the superior retina. Using forceps, the device is inserted gently into the subretinal space where it remains until it is adsorbed. It is known that material injected under the retina, with time, diffuses from that location into the subretinal space under the macula and exerts a therapeutic effect.

Implantation methods are known to one skilled in the art. Implantation may use forceps. Implantation may use an injector.

In one embodiment, the device contains agents that are neuronal cell protective and/or neuronal cell proliferative. The agents can be on the device, in the device, both on and in the device, and/or administered with the device by, e.g., simultaneous or substantially simultaneous injection upon implantation. Such devices are used for implanting in patients with glaucoma, neurodegenerative diseases including dry or wet forms of age related macular degeneration (ARMD), retinitis pigmentosa where the retinal cells and retinal pigment epithelial cells die by aging and genetic/inflammatory predisposition, and diabetic retinopathy.

One non-limiting example of such an agent is rho kinase (ROCK). ROCK plays an important role in cell proliferation, cell differentiation and cell survival/death. Blockade of ROCK promotes axonal regeneration and neuron survival in vivo and in vitro, thereby exhibiting potential clinical applications in spinal cord damage and stroke. ROCK inhibitors attenuated increases in pulmonary arterial pressures in response to intravenous injections of serotonin, angiotensin II, and Bay K 8644. Y-27632, sodium nitrite, and BAY 41-8543, a guanylate cyclase stimulator, decreased pulmonary and systemic arterial pressures and vascular resistances in monocrotaline-treated rats.

Its use to prevent and/or treat in degenerative retinal diseases such as ARMD, retinitis pigmentosa, and glaucoma has not been reported and thus is new. ARMD can have an inflammatory component, contributing to cell death and apoptosis. Oxidative and ischemic injury in ARMD and diabetic retinopathy also contributes to ROCK activation. Because ROCK plays an important role in these processes, inhibiting ROCK can prevent neuronal cell death.

In one embodiment, ROCK inhibitors are injected directly into the eye, e.g., in the vitreous cavity, under the retina, under the choroid, etc. Methods and formulations are disclosed in the following references, each of which is expressly incorporated by reference in its entirety: Peyman et al. Retina 7 (1987) 227; Khoobehi et al., Ophthalmic Surg. 22 (1991) 175; Berger etl al., Investigative Ophthamology & Visual Science, 37 (1996) 2318; Berger etl al., Investigative Ophthamology & Visual Science, 35 (1994) 1923. In one embodiment, ROCK inhibitors are injected in a polymeric formulation to provide a slow release system. In this embodiment, the polymeric material is made from any biodegradable polymer as known to one skilled in the art. Examples of suitable materials include, but are not limited to, polymers and/or co-polymers (poly)lactic acid (PLA), (poly)glycolic acid (PGA), lactic acid, (poly)caprolactone, collagen, etc. These can be injected or implanted in a shape and location as described above. In one embodiment, ROCK inhibitors are administered in a slow release system.

In one embodiment, ROCK inhibitors are administered with one or more other agents that inhibit inflammatory processes, inhibit angiogenesis, and/or inhibit fibrosis. Such agents include, but are not limited to, vascular endothelial growth factor (VEGF) inhibitors, platelet-derived growth factor (PDGF) inhibitors, and integrin inhibitors. In one embodiment, ROCK inhibitors are administered in a non-slow release form, and VEGF, PDGF, and/or integrin inhibitors are administered in a slow release form. In one embodiment ROCK inhibitors are administered in a slow release form, and VEGF, PDGF, and/or integrin inhibitors are administered in a non-slow release form. In one embodiment, ROCK inhibitors and VEGF, PDGF, and/or integrin inhibitors are administered in a dual, triple, or quadruple slow release form.

Examples of ROCK inhibitors include, but are not limited to, the following agents: fasudil hydrochloride (inhibitor of cyclic nucleotide dependent- and rho kinases); GSK 429286 (a selective ROCK inhibitors); H 1152 dihydrochloride (a selective ROCK inhibitor); glycyl-H 1152 dihydrochloride (a more selective analog of H 1152 dihydrochloride); HA 1100 hydrochloride (a cell-permeable, selective ROCK inhibitor); SR 3677 hydrochloride (a potent, selective ROCK inhibitor); Y 39983 dihydrochloride (a selective ROCK inhibitor); and Y 27632 dihydrochloride a selective p160 ROCK inhibitor). VEGF inhibitors include, but are not limited to, Avastin, Lucentes, etc. PDGF inhibitors include, but are not limited to, Sunitinib. Integrin inhibitors are known to one skilled in the art.

The concentration of ROCK inhibitor is administered so that its concentration upon release ranges from less than 1 micromol to 1 millimole. In one embodiment, the concentration of agent is administered so that its concentration upon release ranges from 1 micromole/day to 100 micromol day. Such concentrations are effective and are non-toxic.

The agents may be in any biocompatible formation as known to one skilled in the art. The agents may be formulated as microspheres, microcapsules, liposomes, nanospheres, nanoparticles, etc. as known to one skilled in the art.

The general configuration of the device is new. The device is implanted by any of three different methods in various parts of the eye. In one method, the device is configured for implanting over the lens capsule and between the iris and the lens in the posterior chamber. In one method, the device is configured for implanting in the suprachoroidal space; in this embodiment, agent contained in and/or on or with the device is delivered to the choroid and retina. In one method, the device is configured for implanting in the subretinal space; in this embodiment, agent contained in and/or on or with the device is delivered to the sensory retina.

In an intralens device, the device may be of any shape. The following embodiments are illustrative only and are not limiting. In one embodiment, the device is ring shaped. In one embodiment, the device is shaped as an open ring (e.g., doughnut or tire shape). In one embodiment, the device is shaped as a rod, which may be straight or curved. In one embodiment, the device is shaped as a semicircle. In one embodiment, the device contains one ring. In one embodiment, the device contains at least two concentric rings. In one embodiment, the device is shaped as an oval. In one embodiment, the device is C shaped. In one embodiment, the device is shaped as triangle. In one embodiment, the device is shaped as a quadratic. In one embodiment, the device is spring-shaped. In one embodiment, the device is shaped in a zigzag configuration. A tube structure permits delivery of agent that must be in a liquid medium, such agents include agents for gene modification or stem cells.

In one embodiment, the size of the device ranges from 1 mm in diameter up to about 34 mm in diameter. In one embodiment, the size of the device ranges from 1 mm in diameter up to about 20 mm in diameter. In one embodiment, the thickness of the device may range from about 50 μm to about 3000 μm. In one embodiment, the thickness of the device may range from about 10 μm to about 3000 μm. In one embodiment, the device is made from a polymeric material that is absorbable. In one embodiment, the device is made from a polymeric material that is nonabsorbable, e.g., polylactic acid polyglycolic acid, silicone, acrylic, polycaprolactone, etc. In one embodiment, the device is made as microspheres.

The device is positioned in the lens capsule, e.g., after cataract extraction prior to or after IOL implantation. In one embodiment, it is positioned inside the lens capsule after cataract extraction and acts as a polymeric capsular expander keeping the capsular bag open for intraocular lens (IOL) implantation). In one embodiment, the device is positioned on the haptics of the IOL. In one embodiment, the device is located inside the capsule or under the iris supported by the lens zonules, or it can be sufficiently large to lie in the ciliary sulcus, or ciliary body, or hanging from the zonules in a C-shaped configuration.

For implantation, after removing the lens cortex and nucleus inside the capsule through a capsulotomy, the inventive device is implanted before or after an IOL is implanted. The inventive device is flexible, deformable, and re-moldable. In one embodiment, the inventive device is implanted through a incision one mm or less using an injector, forceps, etc. The incision may be made in the cornea for cataract removal. In one embodiment, the inventive device is implanted in an eye without cataract extraction. In this embodiment the inventive device may be implanted under the iris, e.g., after traumatic anterior segment injury, and lies over the crystalline lens, IOL, and zonules. Implantation may be facilitated by using a visco-elastic material such as healon, methyl cellulose, etc.

Retino-choroidal diseases are aggravated after cataract surgery. Retino-choroidal diseases include, but are not limited to, diabetes, existing prior inflammations such as uveitis, vascular occlusion, wet age related macular degeneration, etc. Patients with these diseases are candidates for the inventive drug delivery system and method. Other indications are prophylactic therapy prior to development of retinal complications, such as inflammation (CME) and infection, and therapy for an existing disease. Other indications are conditions in which any intraocular drug delivery to treat aging processes if cataract surgery is contemplated or after IOL implantation. In latter situation, the inventive device can be implanted in the capsule or over the IOL under the iris Other indications are post-surgical inflammations, post-surgical infections such as after cataract extraction, and any intraocular delivery.

In one embodiment, medication can be coated on a surface and eluted from the surface of the inventive device for delivery, using methods known in the art (e.g., drug-coated stents). In one embodiment, medication can be incorporated in the polymeric material using methods known to one skilled in the art. The following medications can be delivered, alone or in combinations, to treat eyes using the inventive system and method: steroids, non-steroidal anti-inflammatory drugs (NSAIDS), antibiotics, anti-fungals, antioxidants, macrolides including but not limited to cyclosporine, tacrolimis, rapamycin, mycophenolic acid and their analogs, etc. For example, voclosporin (FIG.) is a next generation calcineurin inhibitor, an immunosuppressive compound, developed for the treatment of uveitis, an inflammation of the uvea, the treatment of psoriasis, and for the prevention of organ rejection in renal transplant patients. It can be used with other immunomodulatores, etanercept, infliximab, adalimumab, etc. Other examples include: antibodies (e.g., anti-vascular endothelial growth factor), immunomodulators, antiproliferative agents, gene delivery agents (e.g., to treat damaged neuronal tissue), neuroprotective agents, anti-glaucoma agents (e.g., to treat or prevent increases in intraocular pressure, etc.). In one embodiment, combinations of agents may be provided in a single device or in multiple devices.

The duration of delivery is manipulated so that the agent(s) is released at a quantity needed to achieve therapeutic effect for each agent, if more than one agent is administered, as long as necessary. Duration may be a single dose, may be one day, may be daily for up to 12 months or longer, may be several times a day. In embodiments using a polymer, reimplantation is possible through a small incision once the polymer is absorbed.

Other variations or embodiments will be apparent to a person of ordinary skill in the art from the above description. Thus, the foregoing embodiments are not to be construed as limiting the scope of the claimed invention. 

1. An ocular device comprising a biodegradable, and absorbable body configured in a shape for implanting directly exterior and anterior to a crystalline lens capsule in a patient's eye shaped in a C configuration or a ring configuration to stably lay on zonules or the anterior lens capsule or an intraocular lens (IOL) between an iris and an outer surface of the lens capsule, or in the choroid shaped in straight rod configuration or in a snake-shaped semicircle configuration to follow the inside curvature of the sclera and readily position inside the suprachoroidal space, or under the retina shaped in a rod configuration or a semicircle configuration the device comprising a deformable material such that the device is folded upon implantation, the device optionally containing an ocular therapeutic agent released upon implanting in the patient's eye.
 2. The device of claim 1 sized between 8 mm diameter and 18 mm diameter, inclusive.
 3. A method of treating a patient by administering the device of claim 1 and intravitreally injecting the ocular therapeutic agent.
 4. The device of claim 1 containing a liquid medium in which an agent is suspended.
 5. The device of claim 1 containing a therapeutic agent in the device. 